The Story of Life: Cell–cell Communication in the Pituitary: Orchestrator of Pulsatile Growth Hormone secretion?

How Cells Are Never Alone But Always ‘Hooked Up” in a Network that Determines EVERYTHING They Do

Screenshot 2017-03-15 02.45.48

Direct cell–cell communication in a three-dimensional network of pituitary growth hormone-secreting cells connected by adherens junctions. This challenges the conventional view of endocrine cells as collections of dispersed cells and suggests that physical connectivity mediates cellular responses to coordinate pulsatile secretion.

The Pituitary gland is much like other glands…and furthermore to us, though the research has not been done, much like most other life forms on the planet. The cells that make up the gland are not just, as the researchers here  point out, a “heterogeneous scattered distribution that just dwells in a heap wherever they happen to be seen in our microscopes.

Living in communities is not just something that humans learn through some additive “cultural” development, it goes beyond all organisms..and down to the cell levels within the various tissues and organs in each individual organism  Having an election to decide what we do as a nation or city is very much the way the cells of the pituitary or a biofilm of bacteria jointly decide by their own interconnection how they ALL with work together.

The problem that these authors point out and which has been hobbling research into the endocrine system is that the 2D perspective upon which investigator have had to rely failed to show the reality of the underlying situation, that all Growth Hormone cells, even those that appear in random 2D sections as isolated cells or in small islets , actually form a connected 3D multicellular GH cell system throughout the gland.

To secrete highly ordered GH pulses (up to 1,000-fold rise in hormone levels in vivo), the pituitary GH cell population needs to mount coordinated responses to GH secretagogues,that has no explanation without the understanding of the geometry of connection among all the growth hormone secreting cells in the pituitary. As it is a discrete organ containing a limited number of well-defined, tractable and tissue-restricted cell lineages, the anterior pituitary represents an excellent model for studying the roles of cell networks in endocrine function and hormone release.

These findings change our view of GH cells, from a collection of dispersed cells to a geometrically connected homotypic network of cells whose local morphology and connectivity can vary, to alter the timing of cellular responses to promote more coordinated pulsatile secretion.

As such, the description of these endocrine cell networks alters the concept of the pituitary from a gland which simply responds to external regulation to that of an oscillator which may memorize information and constantly adapt its coordinated networks’ responses to the flow of hypothalamic inputs.

Revealing the large-scale network organization of growth hormone-secreting cells

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1277257/

 

This movie shows the cell positioning of growth hormone (GH)-EGFP cells imaged with two-photon excitation microscopy (z-step: 0.6 mm) and illustrated in Fig. 1A. By following the fluorescent cells during the movie, it is clear that all GH cells are in contact with other fluorescent cells when viewed in 3D.

The functional organization of GH cells that might explain the coordinated responses of the thousands of individual GH cells located within the gland that was not available from previous histological studies that showed most pituitary endocrine cell types merely heterogeneously distributed and scattered throughout the mammalian gland parenchyma in what seemed to be a random mosaic fashion

At present, functional assessment of GH cells is based on cell numbers and activities (1, 2). However, this current concept faces a paradox. The GH cell population in the pituitary produces massive GH pulses in response to physiological needs (up to a thousand-fold increase in GH concentration) (3-5) whereas the pulses are much smaller when GH cells are studied out of their tissue context (6).

We believe that as we have known for decades now with quorum sensing that determines the strategy and intelligent funcional life of bacteria that cells can never be considered as merely individual entities randomly dispersed. Almost everything that happens in all the tissues of our bodies requires  some concerted action by that particular tissue or organ to integragte and relate to actions in the other organs and tissues.  Imagine if all the cells were to function as individual in each organ and not as an orchestra…what would the ‘tune they played sound like”?  And how would that randomness lead to chaos among all the other orchestras playing in the body that signalled each other about their needs or were signaled.  The cells have to be connected and connected tightly in ways that biology and medicine still do not understand.

The neurons are only an  example of the need for coordination into assemblies..and we dont’ even appreciate those because the focus has only been on the obvious synapses. Even in the brain, we find that the astrocytes form a brain wide network vaster than that produced by neurons, with more glia than neurons and most volume accounted for taken by gial than by neurons. These astroctyes, too, are connected and function in pulses in their own rhtym..that underlies and helps the neuron rhythm synchonize with the tune of the astrocyte network  This network likely is very much behind the cooridnation of all neurogenenes as well as much much more…in the brain.  B

But the network functionality depends on connections…via what are known as gap junction and hemi-channels (which are more or less a junction that opens so that it does not connect two cells to each other through a  quick back door..but to the extra cellular fluid.

We have written about this repeatedly of late in our Page and we have to urge readers to get to understand Gap Junctions and the connexins which help form them and the cadherins in the cells which interface with them.  We can promise you that soon you will not be able to understand much of what we write here…and shortly you will not be able to understand anything about neuroscience or medicine if you do not get up to date on these gap junctions and the rhythmic coordination via vast networked that control all aspects of our lives..

Ask us for more sources and references…but whatever you do please do not get left out in the cold without a clue. This is the future and the future is already here now.

Review:  Anterior pituitary cell networks

http://www.sciencedirect.com/science/article/pii/S0091302212000349

These authors add, “Both endocrine and non-endocrine cells of the pituitary gland are organized into structural and functional networks which are formed during embryonic development but which may be modified throughout life. Structural mapping of the various endocrine cell types has highlighted the existence of distinct network motifs and relationships with the vasculature which may relate to temporal differences in their output. Functional characterization of the network activity of growth hormone and prolactin cells has revealed a role for cell organization in gene regulation, the plasticity of pituitary hormone output and remarkably the ability to memorize altered demand”

This large-scale 3D view of cell functioning provides a powerful approach to identify and understand other networks of endocrine cells that are thought to be scattered in situ. Many dispersed endocrine systems exhibit pulsatile outputs. We suggest that cell positioning and associated cell-cell connection mechanisms will be critical parameters that determine how well such systems can deliver a coordinated secretory pulse of hormone to their target tissues.

 

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The video and the research highlighted here suggest that GHRH does not simply affect all cells independently in this region but changes the local pattern of cell-cell communication, resulting in small islets of more highly functionally connected GH cells at some points in the system, interspersed with functionally less connected GH cells.

This paradoxical reduction would “sharpen” the global pulsatile response by minimizing the contribution of less coordinated cell assemblies within the network.

Almost all of the fluorescent (GH) cells were in close contact with other fluorescent cells, seeming to form a homotypic connected 3D cell continuum 

These GH cell assemblies had closely apposed membrane contacts , with junctional complexes immunopositive for β-catenin,  suggesting that the strands and clusters of GH cells are linked with focal adherens junctions.

These results revealed that the geometry of the system varied markedly and reversibly from early postnatal life, through sexual maturation, to late adulthood 

The increase in cluster density coincided with the process of sexual maturation and the increased activity of the GH axis known to occur at this time /

We suggest that intact GH clusters facilitate GH responses to secretagogues, because disaggregation of the GH system by enzymatic dispersion of mature male pituitaries led to a GH release response to GHRH 8-fold lower than that seen from large assemblies of GH cells preserved in pituitary slices (data not shown).

 We note that it is the geometry of the GH cell system, rather than the global cell density, that is organized in a way that would promote a more coordinated pulsatile release of GH that accelerates growth at puberty (

In six of eight fields, the overall number of cell pair connections increased in response to GHRH so that temporally precise calcium spike sequences recurred in synchrony several times; GHRH triggered a profound and sustained stimulation of calcium spiking that was associated with a selective increase in cell connectivity between pairs or triplets of neighboring GH-EGFP cells 

The average periodicity of recurrent motifs of calcium signals detected in these lateral pituitary zones corresponded with the frequency of small GH pulses

Our results unveiled a homologous continuum of GH cells connected by adherens junctions that wired the whole gland and exhibited the three primary features of biological networks: robustness of architecture across lifespan, modularity correlated with pituitary GH contents and body growth, and connectivity with spatially stereotyped motifs of cell synchronization coordinating cell activity.

 

 

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